The major aims of this project have been accomplished through the establishment of a large community-based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are near completion and analyses of the findings are underway. To date, about 600 probands and about 1200 of their relatives have completed the study, including over 150 children between the ages of 7-17. Approximately 600 individuals have also been evaluated at the NIH Clinical Center. Probands represent a large range of disorders including mood, anxiety, sleep, migraine, and cardiovascular in addition to controls. We are now completing interviews with relatives who had not previously participated in the study. During the past year, we have nearly completed recruitment of probands. We have continued to contact additional family members to enhance the participation rate and are remotely collecting measures including activity assessments and saliva for extracting genetics data. We have completed collection and genotyping of DNA samples obtained through the end of 2018, and began statistical genetic analyses. We are also continuing to follow-up families with diagnostic interviews, mobile assessments, and selected clinical assessments to test the stability of these measures over time and track their relationship with emerging mental and medical illness in probands and family members, especially offspring age 30 and under. We completed pilot testing of the computerized version of our diagnostic interview and other study assessments. We plan to complete the transition to computer acquisition of all of the key measures in the study and to develop computer programs to exploit the item-level data from diagnostic interviews and related measures. We have continued to devote substantial effort to the analysis and publication of findings from this study. During the past year, our analyses have been devoted to: (1) familial aggregation and coaggregation of core clinical phenotypes including suicide attempts, ADHD, sleep disorders, and migraine; (2) associations between mood and anxiety disorder subtypes and familial transmission of the core domains underlying mood and anxiety disorders including sleep patterns, cardiovascular risk factors, hypomanic traits, olfactory function, cognitive neuropsychological function, temperamental domains, and startle and autonomic reactivity; (3) cross validation of findings from our family study with that of a parallel family study in Lausanne, Switzerland; and (4) genetic analyses of copy number variation and polygenic risk scores for bipolar disorder (BD), major depression, sleep disorders and patterns, and migraine. In our analyses of biomarkers that were collected on both probands and relatives, we found there were significant associations between overweight and the atypical subtype of depression and an association for BMI/overweight between probands and relatives in our study of familial specificity of atypical depression (Glaus et al, 2019). Another important finding that emerged during the last year was that the familial aggregation of suicide attempts was primarily attributable to comorbid mental disorders including mood, substance and anxiety disorders, and that the familial diathesis underlying social anxiety disorder (SAD) confers an additional elevation in risk of suicide attempts (Ballard et al, 2019). We are following up this finding by evaluating the extent to which people with SAD have increased reactivity to environmental stressors, particularly those of a social nature. We have conducted both methodologic studies of the procedures and analyses of dynamic phenotypes derived from actigraphy and electronic diaries/ecological momentary assessment (EMA), to harmonize data across multiple sites including our collaborative study in Lausanne, Switzerland, Sydney, Australia, Amsterdam, Netherlands, and Hong King, China. We have now published some of the key methodologic and substantive papers on the core domains that can be extracted from EMA including stability, variability and reactivity, combining data from different research actigraphy devices, functional principal component analysis to compare the structure of multiple data sets, and fragmentation models to test stability of particular emotional and physical states (Lamers et al, 2018; Johns et al, 2019). We published the major paper from our mobile technology phenotypes based on combined EMA-Actigraphy that investigates the inter-relationships of motor activity, sleep, mood, and energy (Merikangas et al, 2019). Findings revealed that motor activity patterns have a central role on mood regulation, and subjective energy has a primary influence on motor activity and sleep, and that people with a history of BD have greater cross-domain reactivity. Follow-up of these findings will be critical to test the stability of the findings and the role of environmental influences on mood/anxiety reactivity. We are also analyzing the real time EMA data to identify triggers and precursors of migraine, core features of mood disorder subtypes, core domains that may discriminate ADHD from mania, and the role of sleep in mood disorders, migraine and cardiovascular diseases and risk factors. We are now sharing these procedures with investigators at Yale, University of Toronto, University Hospital Lausanne, and several other sites. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will render an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: The initial findings of our study have major implications for etiology, treatment, course and nosology of mood and anxiety disorders. However, the work requires replication in larger samples, re-assessment to examine stability of the findings, and collaboration with other sites to cover the full range of the spectrum of mood disorders and increase the power of the study. In collaboration with other NIMH Intramural Research Program investigators, we plan to recruit more probands with BD in order to follow-up on our findings regarding the heritability and promising findings regarding circadian rhythm dysregulation as its core feature. We will also place renewed emphasis on enhancing participation of relatives either in person or remotely and longitudinal follow-up of families. We will continue to follow-up the families, particularly those with youth to fulfill the prospective longitudinal questions about the stability, incidence, consequences, course and remission from mood disorders.